The overall goal remains the elucidation of mechanisms that limit the transport of O2 from the atmosphere to the mitochondria in both health and disease. The present proposal continues f to further explore key aspects of O2 transport limitation. During this time, we have developed a theoretical analysis of the basis for O2 supply limitation of maximum Vo2, tested it in many situations in the isolated canine gastrocnemius preparation, and applied it in normal man. We have begun extensions of the basic theory to better understand the relative importance of different steps in affecting O2 movement through the transport pathway. In this proposal, a notable new direction focuses on human diseases such as chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD), and also on animal models of acute and chronic diseases. Here we will apply the lessons learned during the previous grant cycle to better understand limitations to exercise and O2 transport in common serious human disease states with the anticipation that a better understanding will ultimately translate into improved care. Other new directions are to use combinations of physiological, and molecular approaches to study the normal response of the muscle capillary to endurance training and to use hemoglobin solutions to pursue the mechanisms of limited O2 unloading in skeletal muscle. We also plan (collaborative) method development components involving microvascular plasma P02 and 1H magnetic resonance spectroscopy to assess myoglobin O2 saturation. As always, we purposefully combine animal and human research with theoretical modelling on the conviction that each of these elements is essential to a successful research program, enriching each other so that the whole exceeds the sum of its parts.